Pioglitazone Attenuates Sepsis-Associated Acute Kidney Injury by Modulating TLR-4/NF-κB Signaling and Improving Survival and Renal Function

<b>Aim</b>: Sepsis-associated acute kidney injury (SA-AKI) remains a major cause of mortality, driven by inflammation and oxidative stress. Pioglitazone, a PPAR-γ agonist, has demonstrated anti-inflammatory and antioxidant effects beyond glycemic control. This study evaluated its renoprotective efficacy in a rat model of sepsis induced by cecal ligation and puncture (CLP). <b>Methods</b>: Thirty-six female Wistar rats were divided into Control, CLP + Saline, and CLP + Pioglitazone (10 mg/kg/day) groups. Survival was analyzed for 5 days. Renal function (BUN, creatinine, NGAL), oxidative stress (MDA), antioxidant signaling (NRF2), and inflammatory mediators (TNF-α, IL-6, HMGB1, TLR-4, NF-κB) were quantified by ELISA. Tubular epithelial necrosis, luminal debris, dilatation, hemorrhage, and inflammation were semi-quantitatively scored. <b>Results</b>: CLP caused marked renal dysfunction with elevated BUN, creatinine, and NGAL (<i>p</i> all <0.001 vs. Control). Pioglitazone significantly reduced these markers (<i>p</i> < 0.001 vs. CLP + Saline) and improved survival. Plasma MDA levels increased and renal Nrf2 levels decreased following CLP induction (both <i>p</i> < 0.001 vs. Control), whereas pioglitazone treatment significantly reduced MDA levels and increased NRF2 expression (<i>p</i> = 0.002 and <i>p</i> < 0.001 vs. CLP + Saline, respectively). Inflammatory mediators were markedly increased in sepsis (TNF-α, IL-6, HMGB1, TLR-4, and NF-κB; all <i>p</i> < 0.001 vs. Control) and significantly downregulated by pioglitazone (<i>p</i> < 0.01, <i>p</i> < 0.001, <i>p</i> < 0.001, <i>p</i> < 0.01, <i>p</i> < 0.01 vs. CLP + Saline, respectively). Histopathological injury was pronounced in septic rats (all <i>p</i> < 0.01 vs. Control) but was markedly ameliorated by pioglitazone <i>p</i> < 0.05, indicating substantial structural recovery. <b>Conclusions</b>: Pioglitazone markedly ameliorates CLP-induced SA-AKI by suppressing TLR-4/NF-κB/TNF-α signaling and oxidative stress, improving renal structure, function, and survival. These findings support its potential repurposing as a therapeutic adjunct in sepsis management.